Hypertrophic Cardiomyopathy is one of the most common inherited heart diseases, affecting 1:200 people (1). Patients with hypertrophic cardiomyopathy have thickened left ventricles which can lead to life-threatening complications such as arrhythmias, heart failure and sudden death (2). Hypertrophic cardiomyopathy patients may go many years without showing any symptoms, therefore many patients have serious cardiac disease by the time they are diagnosed. Doctors currently diagnose hypertrophic cardiomyopathy by echocardiography or cardiac magnetic resonance imaging. Hopefully in the future, genetic tests will make it easier to diagnose this condition.
Hypertrophic cardiomyopathy is caused by over 1500 different mutations in 11 different genes. All these genes encode proteins that make up the sarcomere or are related to the sarcomere. The sarcomere is the structure responsible for contraction inside muscle cells. Mutations that cause hypertrophic cardiomyopathy are dominant, so parents have a 50% chance of passing a disease-causing mutation on to their children. Population-wide genetic screening could help diagnose hypertrophic cardiomyopathy before patients start to show symptoms, therefore allowing doctors to better treat disease and prevent serious complications such as heart failure.
However, none of the treatments currently available address the genetic cause of hypertrophic cardiomyopathy. This will hopefully change with the rise of gene editing tools such as CRISPR and approved gene therapy medications such as Luxturna (3). The first step to creating better treatments is to better understand how each different mutation causes hypertrophic cardiomyopathy.
Large Hypertrophic Cardiomyopathy Study
The Sarcomeric Human Cardiomyopathy Registry (SHaRe Registry) is a collaborative project that collects clinical and genetic data on thousands of hypertrophic cardiomyopathy patients (4). The goal of the SHaRe registry is to better understand how hypertrophic cardiomyopathy develops. So far, SHaRe researchers have enrolled and tracked 4,591 patients for up to 8 years. Patients are recruited at 8 specialty hypertrophic cardiomyopathy centers in Europe, North America and South America (5). Researchers collect patient data including age, sex, heart function, and any episodes of clinical complications such as cardiac arrest, transplantation, stroke, atrial fibrillation and death. The data is then transferred into a centralized database for analysis.
Age of Diagnosis is Important
Most patients (63%) in the SHaRe cohort were male. This bias towards males developing hypertrophic cardiomyopathy has been found in other studies. The median age of SHaRe patients was 45.8 years, and most patients were white.
Age of diagnosis proved to be very important in this study. Patients diagnosed at a younger age were more likely to become sicker than patients diagnosed at a later stage of life. The SHaRe study found that patients diagnosed with hypertrophic cardiomyopathy when they were less than 40 years of age were more than twice as likely to suffer from serious heart disease, such as heart failure or cardiac arrest, than patients diagnosed over 60 years of age. Furthermore, patients diagnosed with hypertrophic cardiomyopathy in their 20s had a 4-fold higher risk of death than the general US population, and 30% higher risk of death than patients diagnosed at an older age (4).
Hypertrophic Cardiomyopathy Mutations
All patients enrolled in the SHaRe registry were tested for genetic mutations. The results showed that if a patient had a mutation in any of 8 sarcomeric genes (MYBPC3, M7H7, TNNT2, TNNI3, TPM1, MYL2, MYL3 or ACTC), they developed more severe disease than patients with mutations in other genes. Patients with mutations in 1 or more of these 8 genes were twice as likely to develop heart failure, arrhythmias or die than patients with mutations in other genes.
This research highlights 2 factors that can predict the severity of hypertrophic cardiomyopathy: the age of onset of disease symptoms and the presence of pathogenic mutations in 8 sarcomeric genes. Clinicians can use these 2 factors to give patients an accurate prognosis and a better idea of how their disease is likely to progress. Clinicians could also use these 2 factors to decide which patients would benefit from more frequent follow up visits to track disease progression.
This study shows the value of large scale datasets collected by international collaborators. It highlights the need for more research into the pathogenesis of different cardiomyopathy-causing mutations. Cardiovascular biobanks can help provide resources for this research and aid researchers to develop new treatments for hypertrophic cardiomyopathy.
- Semsarian et al. New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy. J Am Coll Card. 2015.
- Cannon et al. Irreversible Triggers for Hypertrophic Cardiomyopathy Are Established in the Early Postnatal Period. J Am Coll Card. 2015
- Luxturna (voretigene neparvovec-rzyl) (Online) Accessed 16 October 2018
- Ho et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018.
- SHaRe: From Care to Cure. A Cardiomyopathy Registry (Online) Accessed 16 October 2018